Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Wind, Sven; Schnell, David; Ebner, Thomas; Freiwald, Matthias; Stopfer, Peter

doi:10.1007/s40262-016-0440-1

Cited by 206HER2/EGFR in Cancer ResearchPharmacogenetics and Drug MetabolismLung Cancer Treatments and Mutations

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

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Wind, Sven, Schnell, David, Ebner, Thomas, Freiwald, Matthias, Stopfer, Peter·2017·Clinical Pharmacokinetics

DOI 10.1007/s40262-016-0440-1PMC PMC5315738

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Abstract

Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.

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Concomitant administration of ritonavir has shown no relevant impact on afatinib pharmacokinetics in healthy male adults.
“concomitant administration of ritonavir, a well-known, potent inhibitor of P-glycoprotein and BCRP (another ATP binding cassette drug transporter inhibitor) has shown no relevant impact on afatinib pharmacokinetics in healthy male adults.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
The Drug–Drug Interactions > Ritonavir section reports no relevant change in afatinib exposure when ritonavir was administered concomitantly with a 40 mg afatinib dose in healthy subjects. The claim omits that dose limitation, and our copy does not specify that the subjects in these studies were male adults. The section also reports increased exposure with a different dosing schedule. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Afatinib is highly soluble across the physiological pH range of 1-7.5 and is not expected to interact with acid-reducing agents.
“Afatinib is highly soluble across the physiological pH range of 1–7.5 and is not expected to interact with acid-reducing agents.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
Smoking status does not impact the pharmacokinetics of afatinib.
“Smoking status does not impact the pharmacokinetics of afatinib”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
P-glycoprotein inducers such as rifampicin can reduce afatinib exposure.
“P-glycoprotein inducers such as rifampicin can reduce afatinib exposure.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]
Afatinib does not relevantly inhibit or induce CYP enzymes, so the risk of interactions with co-administered drugs metabolized by CYP enzymes is thought to be minimal.
“afatinib does not relevantly inhibit or induce CYP enzymes, including those involved in drug metabolism.62 Therefore, the risk of interactions between afatinib and co-administered drugs that undergo CYP enzyme metabolism is thought to be minimal.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [62]

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Background
Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker
Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., & Adolf, G. R. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.197756 · Cited by 865 · cited 6× · see citing works
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BackgroundInfluential
Analysis of Epidermal Growth Factor Receptor Gene Mutation in Patients with Non–Small Cell Lung Cancer and Acquired Resistance to Gefitinib
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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
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Emerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport
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Background
A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours
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Self-citation
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Self-citation
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Self-citation
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Background
Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
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A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer
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Background
Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours
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BackgroundMethodResultInfluentialSelf-citation
A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors
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Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment
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A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors
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A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors
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A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours
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Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors
Awada, A. H., Dumez, H., Hendlisz, A., Wolter, P., Besse‐Hammer, T., Uttenreuther‐Fischer, M., Stopfer, P., Fleischer, F., Piccart, M. J., & Schöffski, P. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9880-0 · Cited by 28 · cited 1× · see citing works
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citation
Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer
Ring, A. E., Wheatley, D. A., Hatcher, H. M., Laing, R. W., Plummer, R., Uttenreuther‐Fischer, M., Temple, G., Pelling, K., & Schnell, D. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1812 · Cited by 26 · cited 1× · see citing works
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citation
Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study
Wiebe, S., Schnell, D., Külzer, R., Gansser, D., Weber, A., Wallenstein, G., Halabi, A., Conrad, A., & Wind, S. (2017) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-016-0359-9 · Cited by 24 · cited 4× · see citing works
“In a single-dose study of afatinib 40 mg in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate [eGFR] 30–59 and 15–29 mL/min, respectively) and healthy matched controls (n = 14) [39], the plasma concentration–time profile of afatinib was similar in both groups.”
BackgroundMethodInfluentialSelf-citation
Phase II, open-label trial to assess QTcF effects, pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors
Molife, L. R., Rudman, S. M., Alam, S. M., Tan, D. S. W., Kristeleit, H., Middleton, G., PROPPER, D. J., Bent, L., Stopfer, P., Uttenreuther‐Fischer, M., et al. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2286-7 · Cited by 18 · cited 6× · see citing works
“To characterise the pharmacokinetics of afatinib in a large number of patients with advanced solid tumours, a meta-analysis of five phase I trials [29–32] and one phase II trial [33] in patients with advanced solid tumours (n = 221) who received afatinib (10–100 mg doses) was performed using non-compartmental analysis…”
BackgroundMethodInfluentialSelf-citation
A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole
Gunzer, K., Joly, F., Ferrero, J.-., Gligorov, J., de Mont-Serrat, H., Uttenreuther‐Fischer, M., Pelling, K., Wind, S., Bousquet, G., & Misset, J. L. (2016) · SpringerPlus · doi:10.1186/s40064-015-1601-7 · Cited by 17 · cited 1× · see citing works
“The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [47], paclitaxel [48], pemetrexed [49], docetaxel”
BackgroundSelf-citation
Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer
Mukai, H., Masuda, N., Ishiguro, H., Mitsuma, A., Shibata, T., Yamamura, J., Toi, M., Watabe, A., Sarashina, A., Uttenreuther‐Fischer, M., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2826-4 · Cited by 16 · cited 1× · see citing works
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome P450 isoenzymes
Song, X., Varker, H., Eichelbaum, M. F., Stopfer, P., Shahidi, M., Wilson, K. L., Kaiser, R., & Finnern, H. W. (2011) · Lung Cancer · doi:10.1016/j.lungcan.2011.01.016 · Cited by 15 · cited 1× · see citing works
“In routine clinical practice, afatinib may offer a number of theoretical advantages compared with first-generation TKIs, notably the lack of CYP-related interaction potential, thereby decreasing the risk of drug–drug interactions [64].”
BackgroundSelf-citation
A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors
Chu, Q. S.-C., Sangha, R. S., Hotte, S. J., Sergenson, G., Schnell, D., Chand, V. K., & Hirte, H. W. (2014) · Investigational New Drugs · doi:10.1007/s10637-014-0139-9 · Cited by 11 · cited 1× · see citing works
“The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [47], paclitaxel [48], pemetrexed [49], docetaxel”
BackgroundSelf-citation
Influence of dose adjustment on afatinib safety and efficacy in patients (pts) with advanced EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC).
Yang, J. C., Ahn, M., Dickgreber, N. J., Halmos, B., Hirsh, V., Hochmair, M. J., Levy, B. P., de Marinis, F., Mok, T. S. K., O'Byrne, K. J., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.8073 · Cited by 11 · see citing works
Self-citation
A Phase I Dose-Escalation Study of Afatinib Combined with Nintedanib in Patients with Advanced Solid Tumors
Gordon, M. S., Springett, G. M., Su, Y. B., Ould-Kaci, M., Wind, S., Zhao, Y., & LoRusso, P. M. (2015) · Future Oncology · doi:10.2217/fon.15.50 · Cited by 10 · cited 1× · see citing works
“[50], vinorelbine [51], temozolomide [52], trastuzumab [53, 54], nintedanib [55], carboplatin [56], paclitaxel/bevacizumab [56], cisplatin/paclitaxel [56, 57] and cisplatin/”
Self-citation
A Phase Ib Open Label Clinical Trial of Continuous Once Daily Oral Afatinib (A) Plus Sirolimus (S) in Patients (Pts) with Egfr Mutation Positive (Egfr M+) Nsclc and/or Disease Progression Following Prior Erlotinib (E) or Gefitinib (G)
Morán, T., Palmero, R., Provencio, M., Insa, A., Majem, M., Reguart, N., Bosch‐Barrera, J., Isla, D., Lee, C. P., Kraemer, S., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu349.27 · Cited by 3 · see citing works
Self-citation

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Sorted by citations

Properties of FDA-approved small molecule protein kinase inhibitors
Roskoski, R. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.03.006 · Cited by 554 · see citing works
Inhibition and induction of CYP enzymes in humans: an update
Hakkola, J., Hukkanen, J., Turpeinen, M., & Pelkonen, O. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02936-7 · Cited by 422 · see citing works
A comprehensive review of protein kinase inhibitors for cancer therapy
Kannaiyan, R., & Mahadevan, D. (2018) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2018.1527688 · Cited by 305 · see citing works
“The ORR was 2% in patients who had progressed on crizotinib only, 9% in patients who had progressed on crizotinib and chemotherapy, 17% in patients who had progressed on 2 ALK TKIs and chemotherapy, and 7% in patients who had progressed on 3 prior TKIs and chemotherapy [135].”
BackgroundInfluential
Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology
Verheijen, R. B., Yu, H., Schellens, J. H. M., Beijnen, J. H., Steeghs, N., & Huitema, A. D. R. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.787 · Cited by 279 · see citing works
“6 ng/mL in those with only Grade 1–2 rash.(29) A consistent relationship between exposure and response has not been found yet for afatinib.”
Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology
Lee, K., Seo, I., Choi, M. H., & Jeong, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103004 · Cited by 251 · see citing works
“The anti-tumor agent afatinib (an ATP-competitive 4-anilinoquinazoline derivative), an irreversible epidermal growth factor receptor tyrosine kinase inhibitor, has proven efficacious in phase III trials in patients with non-small cell lung cancer, which is known as the third most common cause of bone metastases [84].”
Background
Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs
Colclough, N., Chen, K., Johnström, P., Strittmatter, N., Yan, Y., Wrigley, G. L., Schou, M., Goodwin, R. J. A., Varnäs, K., Adua, S. J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1871 · Cited by 241 · see citing works
The Ascension of Targeted Covalent Inhibitors
Singh, J. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02134 · Cited by 210 · see citing works
Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism
Abourehab, M. A. S., Alqahtani, A. M., Youssif, B. G. M., & Gouda, A. M. (2021) · Molecules · doi:10.3390/molecules26216677 · Cited by 204 · see citing works
“[50] also revealed a minimal metabolism of afatinib.”
Background
Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings
Harvey, R. D., Adams, V. R., Beardslee, T., & Medina, P. (2020) · Journal of Oncology Pharmacy Practice · doi:10.1177/1078155220931926 · Cited by 115 · see citing works
“62 In contrast, other EGFR TKIs interact with different CYP enzymes to varying extents, potentially impacting the metabolism of concomitant drugs.”
BackgroundInfluential
Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology
Shah, R. R., & Shah, D. R. (2019) · Drug Safety · doi:10.1007/s40264-018-0772-x · Cited by 99 · see citing works
Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes
Estrada‐Bernal, A., Le, A. T., Doak, A. E., Tirunagaru, V. G., Silva, S., Bull, M. R., Smaill, J. B., Patterson, A. V., Kim, C., Liu, S. V., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3555 · Cited by 84 · see citing works
“The FDA-approved dose of afatinib is 40 mg (orally, once daily) providing a plasma AUCtotal for afatinib of 324 ng hour/mL (31).”
Background
Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications
Shaban, N., Kamashev, D., Emelianova, A., & Buzdin, A. A. (2023) · Cells · doi:10.3390/cells13010047 · Cited by 81 · see citing works
“Its mechanism of action is different from first-generation EGFR inhibitors erlotinib and gefitinib, as afatinib irreversibly inhibits autophosphorylation of EGFR, HER2, and HER4 receptors by forming irreversible covalent bonds with ATP-binding sites (Table 1) [118].”
Background
High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2
Nagano, M., Kohsaka, S., Ueno, T., Kojima, S., Saka, K., Iwase, H., Kawazu, M., & Mano, H. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0991 · Cited by 76 · see citing works
An appraisal of anticancer activity with structure–activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review
Haider, K., Das, S., Joseph, A., & Yar, M. S. (2022) · Drug Development Research · doi:10.1002/ddr.21925 · Cited by 75 · see citing works
Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology
van der Kleij, M. B. A., Guchelaar, N. A. D., Mathijssen, R. H. J., Versluis, J., Huitema, A. D. R., Koolen, S. L. W., & Steeghs, N. (2023) · Clinical Pharmacokinetics · doi:10.1007/s40262-023-01293-9 · Cited by 74 · see citing works
A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors
El–Gamal, M. I., Mewafi, N. H., Abdelmotteleb, N. E., Emara, M. A., Tarazi, H., Sbenati, R. M., Madkour, M. M., Zaraei, S., Shahin, A. I., & Anbar, H. S. (2021) · Molecules · doi:10.3390/molecules26237376 · Cited by 72 · see citing works
“EGFR, HER2, and HER4 have an effect on tumor cell proliferation and are presumed to be overly expressed in many cancer cells [125].”
Background
Structure–Activity Relationship Studies Based on Quinazoline Derivatives as EGFR Kinase Inhibitors (2017–Present)
Șandor, A., Ionuţ, I. A., Marc, G., Oniga, I., Eniu, D. T., & Oniga, O. (2023) · Pharmaceuticals · doi:10.3390/ph16040534 · Cited by 76 · see citing works
Interaction between phytotherapy and oral anticancer agents: prospective study and literature review
Clairet, A., Boiteux-Jurain, M., Curtit, E., Jeannin, M., Gérard, B., Nerich, V., & Limat, S. (2019) · Medical Oncology · doi:10.1007/s12032-019-1267-z · Cited by 67 · see citing works
The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma
Truini, A., Starrett, J. H., Stewart, T. F., Ashtekar, K. D., Walther, Z., Wurtz, A., Lu, D. M., Park, J. H., DeVeaux, M., Song, X., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0780 · Cited by 65 · see citing works
Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the EGFR inhibitors afatinib, erlotinib and osimertinib, the ALK inhibitor crizotinib and the VEGFR inhibitor nintedanib in human plasma from non-small cell lung cancer patients
Reis, R., Labat, L., Allard, M., Boudou, P., Chapron, J., Bellesœur, A., Thomas‐Schoemann, A., Arrondeau, J., Giraud, F., Alexandre, J., et al. (2018) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2018.05.052 · Cited by 64 · see citing works
Expert-Augmented computational drug repurposing identified baricitinib as a treatment for COVID-19
Smith, D. P., Oechsle, O., Rawling, M. J., Savory, E., Lacoste, A. M. B., & Richardson, P. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.709856 · Cited by 62 · see citing works
Comparative review of drug–drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer
Xu, Z., & Li, J. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s194870 · Cited by 58 · see citing works
“Afatinib is a moderate inhibitor of P-gp in vitro,(5,125) but clinical data suggest that changes in plasma concentrations of other P-gp substrates are unlikely to occur due to concomitant administration of afatinib.(120,126)”
Background
Afatinib
Wecker, H., & Waller, C. F. (2018) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-319-91442-8_14 · Cited by 57 · see citing works
The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non‐Small‐Cell Lung Cancer and in Healthy Volunteers
Vishwanathan, K., Dickinson, P. A., Bui, K., Cassier, P. A., Greystoke, A., Lisbon, E. A., Moreno, V., So, K., Thomas, K., Weilert, D. K., et al. (2017) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.1035 · Cited by 55 · see citing works
Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation
van Hoppe, S., Sparidans, R. W., Wagenaar, E., Beijnen, J. H., & Schinkel, A. H. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.01.035 · Cited by 54 · see citing works
Approaches to mitigate the risk of serious adverse reactions in covalent drug design
Baillie, T. A. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2021.1832079 · Cited by 53 · see citing works
A Practical and High-Affinity Fluorescent Probe for Uridine Diphosphate Glucuronosyltransferase 1A1: A Good Surrogate for Bilirubin
Lv, X., Feng, L., Ai, C., Hou, J., Wang, P., Zou, L., Cheng, J., Ge, G., Cui, J., & Yang, L. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01097 · Cited by 53 · see citing works
A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship
Yadav, T., Shaikh, G. M., Kumar, M. S., Chintamaneni, M., & Mayur, Y. C. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.861288 · Cited by 54 · see citing works
EGFR, the Lazarus target for precision oncology in glioblastoma
Lin, B., Ziebro, J. K., Smithberger, E., Skinner, K., Zhao, E., Cloughesy, T. F., Binder, Z. A., O’Rourke, D. M., Nathanson, D. A., Furnari, F. B., et al. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac204 · Cited by 48 · see citing works
Simultaneous and rapid determination of 12 tyrosine kinase inhibitors by LC-MS/MS in human plasma: Application to therapeutic drug monitoring in patients with non-small cell lung cancer
Zhou, L., Wang, S., Chen, M., Huang, S., Zhang, M., Bao, W., Bao, A., Zhang, P., Guo, H., Liu, Z., et al. (2021) · Journal of Chromatography B · doi:10.1016/j.jchromb.2021.122752 · Cited by 48 · see citing works
EGFR inhibitors switch keratinocytes from a proliferative to a differentiative phenotype affecting epidermal development and barrier function
Joly‐Tonetti, N., Ondet, T., Monshouwer, M., & Stamatas, G. N. (2021) · BMC Cancer · doi:10.1186/s12885-020-07685-5 · Cited by 48 · see citing works
Synergistic drug combinations and machine learning for drug repurposing in chordoma
Anderson, E. N., Havener, T. M., Zorn, K. M., Foil, D. H., Lane, T. R., Capuzzi, S. J., Morris, D., Hickey, A. J., Drewry, D. H., & Ekins, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-70026-w · Cited by 44 · see citing works
Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma
Aghai, F., Zimmermann, S., Kurlbaum, M., Jung, P., Pelzer, T., Klinker, H., Isberner, N., & Scherf‐Clavel, O. (2020) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-020-03031-7 · Cited by 42 · see citing works
Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice
Zhang, S., Zhu, L., Jiang, Y., Zhang, J., Xu, R., Xu, Y., Xia, B., & Ma, S. (2016) · Acta Pharmacologica Sinica · doi:10.1038/aps.2016.107 · Cited by 40 · see citing works
CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Bayer, F. P., Gander, M., Küster, B., & The, M. (2023) · Nature Communications · doi:10.1038/s41467-023-43696-z · Cited by 37 · see citing works
Immunotherapy and targeted therapy for lung cancer: Current status and future perspectives
Zulfiqar, B., Farooq, A. V., Kanwal, S., & Asghar, K. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1035171 · Cited by 38 · see citing works
Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience
Ricciuti, B., Baglivo, S., Giglio, A. D., & Chiari, R. (2018) · Therapeutic Advances in Respiratory Disease · doi:10.1177/1753466618808659 · Cited by 38 · see citing works
Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring
Chen, L., Zhang, Y., Zhang, Y., Wang, W.-L., Sun, D.-M., Li, P., Feng, X., & Tan, Y. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.11.006 · Cited by 36 · see citing works
The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma—Letter
Federico, A. D., Filippini, D. M., Dall’Olio, F. G., Conci, N., Minari, R., Tiseo, M., & Ardizzoni, A. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2441 · Cited by 36 · see citing works
Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer
Nakao, K., Kobuchi, S., Marutani, S., Iwazaki, A., Tamiya, A., Isa, S., Okishio, K., Kanazu, M., Tamiya, M., Hirashima, T., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-54804-9 · Cited by 35 · see citing works
Targeting HER2 genomic alterations in non-small cell lung cancer
Zeng, J., Ma, W., Young, R. B., & Li, T. (2021) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2021.04.001 · Cited by 35 · see citing works
“Afatinib (BIBW2992) is a highly selective, potent, irreversible inhibitor for EGFR, HER2 and HER4 kinases 38 , 39 .”
Background
[EGFR-TKI ADR Management Chinese Expert Consensus].
(2019) · Europe PMC (PubMed Central) · doi:10.3779/j.issn.1009-3419.2019.02.01 · Cited by 36 · see citing works
Volumetric absorptive microsampling (VAMS) for the quantification of ten kinase inhibitors and determination of their in vitro VAMS-to-plasma ratio
Zimmermann, S., Aghai, F., Schilling, B., Kraus, S., Grigoleit, G. U., Kalogirou, C., Goebeler, M.-E., Jung, P., Pelzer, T., Klinker, H., et al. (2022) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2022.114623 · Cited by 33 · see citing works
Exposure–Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer
Rodier, T., Puszkiel, A., Cardoso, E., Balakirouchenane, D., Narjoz, C., Arrondeau, J., Fallet, V., Khoudour, N., Guidi, M., Vidal, M., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14091844 · Cited by 32 · see citing works
An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review
Dhiwar, P. S., Matada, G. S. P., Pal, R., Singh, E., Ghara, A., Maji, L., Sengupta, S., & Andhale, G. S. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2204351 · Cited by 33 · see citing works
“Lapatinib is a bind reversibly to both receptors of EGFR and HER2 (Wind et al., 2017).”
Background
Afatinib and Erlotinib in the treatment of squamous-cell lung cancer
Tagliamento, M., Genova, C., Rijavec, E., Rossi, G., Biello, F., Bello, M. G. D., Alama, A., Coco, S., Boccardo, S., & Grossi, F. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1540591 · Cited by 32 · see citing works
“It also inhibits transphosphorylation of HER3 [27].”
Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD
Tu, H.-F., Ko, C., Lee, C., Lee, C., Lan, S.-W., Lin, H.-H., Lin, H.-Y., Ku, C., Lee, D., Chen, I., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3436 · Cited by 31 · see citing works
Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer
Singh, D. D., Lee, H., & Yadav, D. K. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1089066 · Cited by 30 · see citing works
Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines
Keller, S., Zwingenberger, G., Ebert, K., Hasenauer, J., Wasmuth, J., Maier, D., Haffner, I., Schierle, K., Weirich, G., & Luber, B. (2018) · Molecular Oncology · doi:10.1002/1878-0261.12170 · Cited by 29 · see citing works
“Published by FEBS Press and John Wiley & Sons Ltd. tumors (Wind et al., 2016).”
Method
EGFR-TKIs in Non-Small-Cell Lung Cancer: Focus on Clinical Pharmacology and Mechanisms of Resistance
Fogli, S., Polini, B., Re, M. D., Petrini, I., Passaro, A., Crucitta, S., Rofi, E., & Danesi, R. (2018) · Pharmacogenomics · doi:10.2217/pgs-2018-0038 · Cited by 29 · see citing works
Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer
Megino‐Luque, C., Moiola, C. P., Molins-Escuder, C., López-Gil, C., Gil‐Moreno, A., Matías‐Guiu, X., Colás, E., & Eritja, N. (2020) · Cancers · doi:10.3390/cancers12102751 · Cited by 28 · see citing works
“Afatinib is a potent, selective, and irreversible ErbB family blocker that covalently binds to the TKD of the receptor and blocks signalling from all ErbB family members, causing tumour growth inhibition and regression [50].”
Background
Reactive metabolite of gefitinib activates inflammasomes: implications for gefitinib-induced idiosyncratic reaction
Kato, R., Ijiri, Y., Hayashi, T., & Uetrecht, J. (2020) · The Journal of Toxicological Sciences · doi:10.2131/jts.45.673 · Cited by 28 · see citing works
“…in this study were similar to their therapeutic concentrations (afatinib, 0.03-0.3 μM; dacomitinib, 0.03-0.3 μM; erlotinib, 1-10 μM; gefitinib, 0.3-3 μM; osimertinib, 0.3-3 μM) (Takahashi et al., 2012; Kobayashi et al., 2016; Planchard et al., 2016; Wind et al., 2017; Endo-Tsukude et al., 2018).”
Influential
Integration of liquid biopsy and pharmacogenomics for precision therapy of EGFR mutant and resistant lung cancers
Kolesar, J., Peh, K. H., Thomas, L., Baburaj, G., Mukherjee, N., Kantamneni, R., Lewis, S. C., Pai, A., Udupa, K., Kumar, N. A. N., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01534-8 · Cited by 30 · see citing works
“Afatinib is the only EGFR TKI that is not metabolized via the CYP450 sys-tem due to its strong covalent binding to plasma proteins and is primarily excreted through the feces [170, 171].”
Background
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Method
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Method
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“In contrast, rifampicin is a potent inducer of ABCB1, and if administered for 7 days before a 40-mg dose of afatinib, decreased AUC by 34 % (94).”
Influential
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Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict PET Image Quality of Three Generations EGFR TKI in Advanced-Stage NSCLC Patients
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“For afatinib, EGFR binding had the highest influence on tumor distribution in the mechanistical PBPK model due to its low dissociation constant (KD) [9,10]: EGFR binding showed the highest contribution to the overall tissue uptake.”
Background
Treatment effectiveness and tolerability of afatinib at different doses in patients with EGFR-mutated lung adenocarcinoma: How low can we go?
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Polypharmacy among older advanced lung cancer patients taking EGFR tyrosine kinase inhibitors
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BackgroundInfluential
Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity
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BackgroundInfluential
Impact of Asian ethnicity on outcome in metastatic EGFR‐mutant non–small cell lung cancer
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Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways
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“Both mTOR complex 1 inhibitor, Everolimus [79, 94] and EGFR receptor kinase inhibitor Afatinib [95] were found to reduce tumour size and load with Everolimus completely abolishing tumour formation in 140-day old cerebral organoids.”
Background
Bypassing P-glycoprotein mediated efflux of afatinib by cyclodextrin complexation – Evaluation of intestinal absorption and anti-cancer activity
Parvathaneni, V., Elbatanony, R. S., Shukla, S. K., Kulkarni, N. S., Kanabar, D. D., Chauhan, G., Ayehunie, S., Chen, Z., Muth, A., & Gupta, V. (2020) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2020.114866 · Cited by 17 · see citing works
Neoadjuvant afatinib with paclitaxel for triple-negative breast cancer and the molecular characteristics in responders and non-responders
Lin, P., Tseng, L., Lee, Y., Chen, S., Yeh, D., Dai, M., Liu, L., Wang, M., Lo, C., Chang, S., et al. (2022) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2022.05.015 · Cited by 16 · see citing works
Topical JAK inhibition ameliorates EGFR inhibitor–induced rash in rodents and humans
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Afatinib in patients with solid tumors with neuregulin 1 (NRG1) fusions: a case series from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study
Rodon, J. A., Rothe, M., Mangat, P. K., Garrett-Mayer, E. S., Cannon, T. L., Hobbs, E. A., Kalemkerian, G. P., Hinshaw, D. C., Gregory, A., Grantham, G. N., et al. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.104545 · Cited by 15 · see citing works
Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update
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Drug–Drug Interactions in the Treatment of Cancer-Associated Venous Thromboembolism with Direct Oral Anticoagulants
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“However, as the drug concentration of afatinib needed to obtain an P-gp inhibiting effect in vivo is 20 times higher than the drug concentration normally seen during clinical use, 28 we did not classify afatinib as a clinically relevant P-gp inhibitor.”
Background
Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors
Mukherjee, S., Joshi, V., Reddy, K. P., Singh, N., Das, P., & Datta, P. (2024) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2024.100980 · Cited by 15 · see citing works
Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer
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Determination of intracellular anlotinib, osimertinib, afatinib and gefitinib accumulations in human brain microvascular endothelial cells by liquid chromatography/tandem mass spectrometry
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Simultaneous and Rapid Determination of Six Tyrosine Kinase Inhibitors in Patients with Non-Small Cell Lung Cancer Using HPLC-MS/MS
Liu, Y., Liu, H., Xia, Z., Wang, Z., Yun, Y., Zhang, G., Huang, L., Gao, S., & Chen, W. (2021) · International Journal of Analytical Chemistry · doi:10.1155/2021/5524361 · Cited by 15 · see citing works
Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure–Response Analyses of a Pivotal Phase I/II Study
Gupta, N., Largajolli, A., Witjes, H., Diderichsen, P. M., Zhang, S., Hanley, M. J., Lin, J., & Mehta, M. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2622 · Cited by 15 · see citing works
Pyrimidine-based dual-target inhibitors targeting epidermal growth factor receptor for overcoming drug resistance in cancer therapy(2006-present)
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Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer
Yokota, H., Sato, K., Sakamoto, S., Okuda, Y., Asano, M., Takeda, M., Nakayama, K., & Miura, M. (2021) · Biology · doi:10.3390/biology10101054 · Cited by 14 · see citing works
“Approximately 85% of afatinib is excreted into the bile as unchanged drug [15].”
BackgroundInfluential
Assessment of Skin Toxicity in an in Vitro Reconstituted Human Epidermis Model Using Deep Learning
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Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies
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Current management of uncommon EGFR mutations in non-small cell lung cancer
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High-throughput kinetics in drug discovery
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Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer
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Investigation on the interaction behavior of afatinib, dasatinib, and imatinib docked to the BCR-ABL protein
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“Conversely, afatinib blocked the ErbB [19] family of tyrosine kinase proteins (the molecules responsible for covalently binding to epidermal growth factors) irreversibly [20, 21].”
Background
Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum
Ishikawa, E., Yokoyama, Y., Chishima, H., Kuniyoshi, O., Sato, I., Nakaya, N., Nakajima, H., Kimura, M., Hakamata, J., Suehiro, N., et al. (2022) · Journal of Chromatography B · doi:10.1016/j.jchromb.2022.123245 · Cited by 12 · see citing works
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“It also provides physical stability to lipid-based systems and pro-longs circulation time. is mainly determined by covalent interactions with plasma proteins, rather than metabolism [79], which differentiates it from non-covalent drugs.”
Background
Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells
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In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans
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Pharmacokinetics of Afatinib, a Selective Irreversible ErbB Family Blocker, in Patients with Advanced Solid Tumours
Wind, S., Schmid, M., Erhardt, J., Goeldner, R.-G., & Stopfer, P. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-013-0091-4 · Cited by 94 · see citing works
Self-citation
Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors
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Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
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Self-citation
Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study
Wiebe, S., Schnell, D., Külzer, R., Gansser, D., Weber, A., Wallenstein, G., Halabi, A., Conrad, A., & Wind, S. (2017) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-016-0359-9 · Cited by 24 · see citing works
Self-citation
Pharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir
Wind, S., Giessmann, T., Jungnik, A., Brand, T., Marzin, K., Bertulis, J., Hocke, J., Gansser, D., & Stopfer, P. (2014) · Clinical Drug Investigation · doi:10.1007/s40261-013-0161-2 · Cited by 63 · see citing works
Self-citation

Authors: Wind, S., Schnell, D., Ebner, T., Freiwald, M., & Stopfer, P.
Affiliations: Boehringer Ingelheim (Germany) (DE)
Corresponding author: Wind, Sven
ORCID: Wind, Sven
Ebner, Thomas
Stopfer, Peter
Venue: Clinical Pharmacokinetics
Publisher: Springer Science and Business Media LLC
Published: 2016-07-28
Volume: 56
Issue: 3
Pages: 235-250
ISSN: 0312-5963 (ISSN-L)
1179-1926
DOI: 10.1007/s40262-016-0440-1
PMC: PMC5315738
OpenAlex: W2484071785
Cited by: 206
References: 53
Citations by year: 2026: 14 · 2025: 23 · 2024: 21 · 2023: 28 · 2022: 35 · 2021: 18 · 2020: 24 · 2019: 15 · 2018: 17 · 2017: 9 · 2016: 1
FWCI: 1.41
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0 (unspecified)
Locations: Clinical Pharmacokinetics (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Funders: Boehringer Ingelheim
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: afatinib, EGFR, HER2, ErbB4, pharmacokinetics, pharmacodynamics, food effect, dose proportionality, renal dysfunction, P-glycoprotein, drug-drug interactions, covalent protein adducts, drug-induced arrhythmia, interindividual variability, advanced solid tumors
MeSH terms: Afatinib, Animals, Drug Interactions, Humans, Kidney, Liver, Neoplasms, Protein Binding, Quinazolines, Radiation-Sensitizing Agents, ATP Binding Cassette Transporter, Subfamily B, Member 1, Protein Kinase Inhibitors, ErbB Receptors

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